The overall goal of this proposal is to clone a tumor suppressor gene involved in the development of the most aggressive form of endometrial cancer, ulterine papillary serous carcinoma (UPSC). Cancer of the endometrium is the most common gynecologic malignancy in the U.S., with an estimated 33,000 new cases each year. Although UPSC accounts for greater than 10 percent of all endometrial cancers, it is responsible for more than half of all endometrial cancer mortality. UPSC and serous carcinoma of the ovary are histologically indistinguishable. They show similar patterns of metastatic spread and it has been suggested that serous cancers of the endometrium and ovary originate from a common cell type. We have shown that approximately 65 percent of uterine papillary serous carcinoma have loss of heterozygosity (LOH) of the 1p32-p33 region. The frequency and regional specificity of deletion speaks to the involvement of a novel tumor suppressor gene. Discovery of the 1p tumor suppressor gene involved in UPSC tumorigenesis is important first step toward further biochemical and biological investigation of serous carcinomas. The methods proposed to clone the 1p UPSC tumor suppressor genes are as follows: I. Further define the minimum region of deletion on 1P in uterine papillary serous carcinomas. The UPSC tumor suppressor gene has been mapped to a small region, flanked by the markers D1S190 and D1S447. We will develop a complete clone contig spanning the region of deletion and new polymorphic markers will be devised. LOH mapping studies will be performed in an expanded collection of tumors in an effort to further refine the minimum consensus region of deletion. II. Identify and characterize candidates for the 1p UPSC tumor suppressor gene. Several methods will be used to identify candidate genes and determine whether they are involved in the development of UPSC. EST and cDNA mapping, large scale genomic sequencing, direct selection of cDNAs, and exon trapping will be used to identify candidates. Tumors will be investigated for mutations in candidate genes using PCR and single strand conformational variant analysis. The proposed studies will lead to the development of a transcript map for the UPSC deletion region and the discovery of a UPSC tumor suppressor gene.